Case 1
You receive a notice from the state newborn screening office that a newborn in your practice has a very high level of 17-hydroxyprogesterone and is suspected of having congenital adrenal hyperplasia. Your nurse contacts the parent to bring the child to the local Emergency Department right away. When seen in the ED, the 1-1/2 week old male appears lethargic. Since his hospital discharge at 2 days of age, the child has had several episodes of vomiting. At the suggestion of the grandmother, the infant has been fed goat’s milk for the past 3 days. There is no history of fever, diarrhea, or respiratory symptoms. He has had only 1 wet diaper today. Perinatal history is unremarkable except for the lack of prenatal care. The child was born at term with a birth weight of 3.2 kg. The maternal family history is negative; paternity is uncertain and the paternal family history is unknown.

Exam: Weight 2.8 kg (12.5% lost since birth); length 48 cm. The child is lethargic but responds to tactile stimulation. When aroused, he appears irritable and difficult to console. The anterior fontanel is sunken and the oral mucosa appears sticky. He is moderately tachycardic at rest without a murmur or irregular rhythm. The abdomen is soft and non-tender. The genitalia are normal without evidence of virilization. Both testes are palpable. Other than the lethargy, his neurological exam is normal. The skin is cool to the touch with a capillary refill of 4 seconds.

A presumptive diagnosis of adrenal insufficiency with salt wasting secondary to congenital adrenal hyperplasia (CAH) is made. Because of the elevated serum potassium, an EKG is ordered which demonstrates prominent T-waves with a normal cardiac rhythm.

The infant is given a rapid 20 ml/kg bolus of normal saline (0.9% NaCl solution), followed by D5NS at 1.5 times maintenance. Potassium is avoided in the IVF. He is also given a 25 mg of IV hydrocortisone. Following the bolus of IVF he improves clinically. After conferring with a pediatric endocrinologist, confirmatory blood tests are drawn and sent to the hospital lab. A repeat chemistry panel 4 hours later shows a Na 134 mmol/L, K 5.2 mmol/L, Cl 98 mmol/L, bicarb 18 mmol/L, and glucose 80 mg/dL. The infant is admitted to the ICU for further stabilization, treatment and monitoring. Social Service is asked to assist with anticipated long term medication needs and follow-up medical care. and the Endocrine Service consulted to help direct future care, education of the mother and outpatient follow-up.

Case 2
A 9 year old female is brought to your office by her parents with a chief complaint of thickened nails. The thickened nails have been present for over six months and have not responded to topical ointments. Two visits to a podiatrist also failed to clear the problem. Having agreed to perform in an upcoming hula performance (in her bare feet), she is increasingly anxious about the appearance of her toes.

Her past medical history is negative. Review of systems is positive for a tanned complexion (even with only average sun exposure) and for intermittent complaints of lower leg cramps. The leg cramps are, at times, quite painful but resolve spontaneously after 1 to 2 minutes of rest and massage. The cramps occur irrespective of her activities and were diagnosed by a local practitioner last year as growing pains. Both parents are Swedish born, having migrated to the United States just shortly before the patient's birth. She has an older sister, aged 16 years, who is quite tall and post-menarchal. The parents and sister have a fair skin complexion. There has been no recent travel.

Exam: Vital signs: T37, P80, R25, BP 90/70. Height and weight are both at the 50th percentile. HEENT, cardiac, pulmonary, and abdominal exams are unremarkable. Breasts and genitalia are Tanner stage I. Neurological evaluation is normal with no focal findings. She has a generalized tan even in areas that are unexposed to sun. Her nails are thickened and brittle (8 of the 10 toenails and 4 of the 10 fingernails) consistent with a chronic fungal infection (see Figure 1 below).

Figure 1. Onychomycosis

Clinical diagnosis and treatment: Addison's disease is suspected on the basis of the tanned complexion and the onychomycosis. An 8 AM serum cortisol level is low and an ACTH level is high. Treatment with oral hydrocortisone replacement is initiated.

The adrenal gland consists of two embryologically distinct regions: an external adrenal cortex and an inner adrenal medulla. The adrenal cortex serves a vital role in the production of endocrine hormones, specifically mineralocorticoids (aldosterone), glucocorticoids (cortisol), and sex steroids (androgens), while the adrenal medulla produces catecholamines (epinephrine and norepinephrine) in response to stress. In general, disorders of the adrenal cortex occur when the production of one or more of these hormones is insufficient or in excessive. Such conditions can be either congenital or acquired.

The biochemical pathway within the adrenal cortex begins with cholesterol which is converted into aldosterone, cortisol, and adrenal androgens. ACTH (adrenocorticotropic hormone) stimulates the production of cortisol producing a negative feedback which, in turn, modulates ACTH production.

The manifestations of adrenal insufficiency (AI), including hypotension, hypoglycemia, electrolyte imbalance (hyponatremia and hyperkalemia), dehydration, and acidosis, can be life threatening. In children, AI may be present from birth (congenital) or acquired (e.g., Addison’s disease).

Congenital adrenal insufficiency The salt-losing form of CAH, as illustrated in Case #1, is by far the most common congenital form of AI. Approximately 95% of CAH is caused by a deficiency of the 21-hydroxylase enzyme (21-OHase CAH) inherited as an autosomal recessive disorder. Inherited deficiencies of other enzymes involved in cortisol and aldosterone production, such as 11-OHase and 17-OHase, are rare. Deficiency of the latter enzymes is associated with hypertension rather than salt loss, due to accumulation of aldosterone precursors which, when present in abnormally high levels, results in salt retention.

The 21-hydroxylase enzyme is required to convert steroid precursors into both cortisol and aldosterone. In congenital adrenal hyperplasia (CAH) 21-hydroxylase deficiency with salt wasting, cortisol production is deficient resulting in hyponatremia, hyperkalemia, hypoglycemia, and high ACTH levels. Salt wasting is confirmed by a high urinary sodium despite hypontremia. Similarly, aldosterone deficiency leads to elevated levels of plasma renin. In the non-salt-wasting variety of CAH, the aldosterone pathway remains intact, although renin levels may be inappropriately elevated, suggesting inefficient mineralocorticoid production. In both types of CAH, however, elevated levels of ACTH stimulate the biochemical pathway of the adrenal cortex, shunting hormone production away from cortisol and towards an excess accumulation of various androgenic precursors, such as androstenedione and testosterone, which lead to virilization as in Figure 2 below.

Infants with classic 21-OHase CAH usually present with virilization (obvious in females, more subtle or absent in males), hypotension, hyponatremia, hyperkalemia, and hypoglycemia. The infants demonstrate intolerance to formula feedings, vomiting, and weight loss frequently as a result of their acidosis. This can lead to severe dehydration and death if undetected or inadequately treated. Approximately two-thirds of children with classic 21-OHase deficiency present with salt-loss within the first 2 to 3 weeks of life. Children with non-salt losing 21-OHase CAH come to medical attention at a later age, generally after developing premature virilization, such as the presence of an adult-like body odor, acne, pubic hair, and/or axillary hair. As a consequence, children with non-salt losing CAH, also known as simple virilizing CAH, may remain unrecognized for years until clinical signs of premature virillization become evident. A rare condition that may mimic salt-losing CAH is pseudohypoaldosteronism. This aldosterone disorder is caused by a defect at the aldosterone receptor site. Although affected infants also exhibit hyponatremia and hyperkalemia, unlike infants with 21-OHase CAH, those with pseudohypoaldosteronism are not virilized, have elevated rather than deficient blood levels of aldosterone and have either normal, or mildly increased adrenal androgen concentrations (e.g., 17-hydroxyprogesterone, androstenedione, and dihydroepiandrosterone sulfate) due to the associated stress.

The typical infant with salt-losing CAH presents with dehydration and signs of hypovolemia, with or without peripheral vascular collapse, sometime between the 3rd and 28th day of life. Although uncommon, such signs may be delayed for as long as 3 to 4 months in premature infants receiving supportive salt-containing intravenous fluids plus corticosteroids. Male infants with classical salt-losing CAH tend to have normal appearing external genitalia at birth. In contrast, females with this condition characteristically demonstrate virilized external genitalia (i.e., ambiguous genitalia) at the time of birth due to a prolonged intrauterine exposure to excessive adrenal androgens. Although CAH is inherited as an autosomal recessive disorder, historically an unexpected majority (greater than 60%) of infant females with CAH were reported with the disease. These observations suggested that a substantial number of male infants with CAH were being undiagnosed, many of whom were thought to have died from other causes such as SIDS. As would be expected, recent data from the newborn screening program demonstrates no gender difference. The successful implementation of state newborn screening programs has significantly improved the detection and survival of all children with classical CAH, especially males.

Genetic mutations leading to CAH have been mapped to the class III region of the HLA (human leukocyte antigen) complex (specifically HLA-B and HLA-DR) located on chromosome 6. Subsequent work has successfully defined the 21-OHase gene structure demonstrating that children with classic 21-hydroxylase deficiency, both with and without salt loss, have a similar genetic abnormality. Although located at the same genetic locus as salt losers, children with the simple virilizing form of 21-OHase deficiency carry a different and distinct allelic abnormality, a genetic pattern analogous to that seen with hemoglobin S and C diseases.

The diagnosis of CAH is established by laboratory findings of a low cortisol in the presence of elevated levels of ACTH and adrenal androgens, the latter either obtained randomly or after stimulation with synthetic ACTH. The elevation of 17-hydroxyprogesterone (17-OHP) is detected on the newborn screen, which only screens for the 21-OHase deficiency form of CAH. Confirmation of the diagnosis includes repeating the 17-OHP, and can include molecular testing. In addition, children with salt-wasting demonstrate hyponatremia and hyperkalemia in association with a low level of aldosterone and an elevated plasma renin activity. As opposed to the low concentration of urinary sodium found in most cildren with hyponatremia secondary to inadequate intake during diarrheal disease (total body sodium depletion), the urine sodium in salt wasting states, such as is seen with mineralocorticoid deficiency or resistance, will be inappropriately high.

Acquired adrenal insufficiency Adrenal insufficiency (AI) can also be acquired, such as in Case #2. Addison's disease classically refers to acquired adrenal insufficiency, historically caused by tuberculosis. With improved healthcare and improved treatment of tuberculosis, autoimmune destruction of the adrenal cortex has become the leading cause of acquired AI. Less common causes of AI include congenital adrenal hypoplasia, fulminant sepsis, adrenal hemorrhage, and inadequate replacement of adrenocortical hormones after surgical removal of one or both of the adrenals. Secondary AI (i.e., lack of ACTH stimulation of the adrenal cortex), most commonly occurs following inadequate tapering of corticosteroids in children treated with long-term, suppressive doses of corticosteroids. Rare forms of secondary AI are associated with a variety of conditions affecting the hypothalamic-pituitary region of the brain, most commonly mid-line birth defects such as children with cleft lip and palate, and septo-optic dysplasia. Children with secondary AI should be investigated for associated deficiencies of other pituitary hormones.

Autoimmune destruction of the adrenal gland (i.e., Addison's disease) may occur either as an isolated phenomenon or, as part of a generalized, autosomal dominant polyglandular autoimmune syndrome (PAS). Several distinct clusters of endocrine hormone abnormalities have been described in PAS. (See below). Children with Type I PAS characteristically present at a young age with complaints of recurrent oral thrush and chronic onychomycosis from the associated T-cell immune dysfunction. Both finger and toe nails can be affected; the nails becoming opaque, thickened, friable and brittle. The characteristics of the 2 types of PAS are listed below:

Secondary adrenal insufficiency is common following iatrogenic suppression of the hypothalamic-pituitary-adrenal axis. Given the widespread use of corticosteroids as anti-inflammatory agents in the treatment of such conditions as asthma, arthritis, autoimmune disease, and/or as adjunctive chemotherapy, iatrogenic secondary adrenal insufficiency is at present, likely the most common cause of AI. Supraphysiologic dosages of exogenous corticosteroids for periods as short as 4 weeks have been associated with the prolonged (up to one year) inhibition of endogenous ACTH-mediated cortisol production.

When temporally associated with an acute event (e.g., adrenal hemorrhage from sepsis-induced disseminated intravascular coagulation), the clinical presentation of acquired AI can be very insidious and nonspecific, requiring vigilance on the part of the healthcare team. Unless the clinician maintains a high index of suspicion, symptoms of AI such as lethargy, fatigue, postural hypotension, and hypoglycemia are easily missed. Generalized hyperpigmentation, as can be seen in primary AI, is absent in secondary AI.

Treatment Patients with acute AI may present with hypothermia, peripheral vascular collapse, and shock. Vital signs, including blood pressure, pulse, respiratory rate, and temperature must be monitored frequently until the child is clinically stable. In addition, continuous EKG monitoring is recommended for potentially life threatening cardiac dysrhythmias. Children who do not respond to the initial fluid challenges with an increase in blood pressure, improved peripheral perfusion, and urinary output should have a central venous catheter placed to monitor central venous pressure.

Serum electrolytes (Na, K, Cl, and bicarbonate) must be obtained immediately upon arrival and followed at 2 to 4 hour intervals for at least the first 24 hours of management. Prior to the start of therapy, if possible, blood should also be obtained for ACTH, androstenedione, 17-OHP, and plasma renin. The 17-OHP serum assay has been shown to be a reliable test for congenital adrenal hyperplasia, even in acutely ill infants. In older children suspected of AI, a blood sample for serum cortisol and ACTH levels should be obtained prior to the initiation of corticosteroid therapy. In children with primary AI, the cortisol level will be low, whereas the ACTH level will be very elevated due to a lack of negative pituitary feedback. Treatment should not be delayed; however, if blood samples are difficult to obtain and/or the child is clinically unstable, blood samples can be considered at a later time.

The initial treatment is aimed at restoring the intravascular volume, correcting the acidosis and electrolyte imbalance, and replacing cortisol. Intravenous fluid therapy must be continued until the child is clinically stable and tolerating adequate oral intake.

For initial hormonal replacement therapy, a glucocorticoid such as IV hydrocortisone, or its therapeutic equivalent (see table 1), must be administered intravenously as a 1 to 2 mg per kg bolus. In generally the initial bolus doses of IV hydrocortisone are: Age 0 to 3 years, 25 mg; 4 to 9 years, 50 mg; 9 to 12 years, 75 mg; >12 years, 100 mg. The initial bolus dose of glucocorticoid should continued every 6 hours. The half-life of hydrocortisone is approximately 60 to 90 minutes and its duration of action is about 4 hours. Once the child is clinically stable and able to resume oral intake, oral corticosteroid replacement can begin. Children with CAH may require a slightly higher daily dose to avoid excessive adrenal androgen production. All children treated with glucocorticoids should be followed to assure treatment is sufficient and not excessive.

Table 1. Glucocorticoid Potency Equivalency

Cortisone

25 mg

Hydrocortisone

20 mg

Prednisone

5 mg

Prednisolone

5 mg

Methylprednisolone

4 mg

Dexamethasone

0.75 mg

Presently there are no parenteral medications available for mineralocortocoid replacement. Hydrocortisone has some mineralocorticoid activity. Textbooks in the past described mineralocorticoid replacement acutely with DOCA (deoxycorticosterone acetate); however this is no longer available for clinical use. In general, adequate rehydration with normal saline will help improve the hyponatremia as well as lower the serum potassium. Once oral intake is resumed, fludrocortisone acetate (Florinef), 0.05 to 0.2 mg/day is given in 1 to 2 doses daily.

Intravenous potassium should be avoided in the first 24 hours unless the serum potassium level drops below 3.5 mmol/L. Children who present with or develop signs of hyperkalemic induced EKG changes must be treated aggressively to avoid cardiac dysrhythmia. If indicated, calcium can be given intravenously to immediately reverse a serious dysrhythmia due to hyperkalemia, but this is temporary and the serum potassium level must be reduced to safer levels. Temporizing measures include the IV administration of sodium bicarbonate, insulin and glucose and/or, aerosolized albuterol. These agents lower the serum potassium quickly by driving the potassium intracellularly (redistribution). Potassium can be removed from the body by exchanging it with sodium via the administration of sodium polystyrene sulfonate (Kayexalate®) resin which can be given orally or as a retention enema. Furosemide can help to excrete potassium as well.

The acute manifestations of AI usually improve by the second day of therapy. Infants with AI may require prolonged oral sodium replacement which can be given as a supplement added to the daily feedings. Older children should be allowed free access to salt and salty foods, especially during hot weather.

During the long-term management of children with CAH, insufficient glucocorticoid results in excess ACTH stimulation of the adrenals, while over production of androgen produces virilization and a premature growth spurt followed by maturation of the growth plates causes resulting in a decrease in the child’s final adult height. Alternatively, excess glucocorticoid results in clinical findings of hypercortisolism, such as central weight gain, cutaneous striae, hypertension, and growth suppression. In addition to clinical findings and measurement of weight and BP, adrenal androgens (17-OHP and androstenedione) are monitored to assess the adequacy of treatment. Elevated levels of adrenal androgens indicate either the need to increase the amount of glucocorticoid given or inadequate compliance. The adequacy of mineralocorticoid replacement may be monitored by measuring serum electrolytes and plasma renin activity. An elevated renin level, especially in children who are hyponatremic, suggests a need for additional mineralocorticoid replacement, salt replacement, or better compliance. With excessive mineralocortocoid therapy, hypokalemia, hypertension, and/or a suppressed plasma renin activity are commonly present.

Glucocorticoid excess Other disorders affecting the adrenal gland in the pediatric population, such as glucocorticoid excess or hypercortisolism are less common. Cushing's syndrome is a symptom complex that reflects an excessive, peripheral adrenal glucocorticoid effect. This type of hypercortisolism may be iatrogenic or endogenous, the latter resulting either from autonomous adrenal hyperactivity (ACTH-independent), or secondary to excess ACTH stimulation (ACTH-dependent) from the pituitary, or rarely an ectopic source. When caused by excessive pituitary ACTH production, the condition is called Cushing's disease.

Cushing's syndrome is most commonly iatrogenic, a result of exogenously administered corticosteroid used as therapy for a variety of medical conditions. Symptoms of hypercortisolism from any cause are typically subtle, often nonspecific and develop slowly. Common findings consist of an increased subcutaneous fat deposition, especially in the temporal areas of the face (producing the so called "moon facies"), the posterior neck ("buffalo hump"), and the abdomen. These findings, however, are also seen in children who are overweight or obese. Other symptoms of hypercortisolism include facial plethora, easy bruising, cutaneous atrophy and striae, elevated blood pressure and, in children and adolescents, growth failure. This latter characteristic, especially when associated with excessive weight gain, is the most common presentation of Cushing's syndrome in the pediatric population. Although not limited to Cushing's syndrome, a deceleration of linear growth velocity is a helpful diagnostic sign in helping differentiate hypercortisolism from exogenous obesity, since children who are overweight or obese often have growth acceleration rather than a slowing of linear growth. In children under 8 years of age, Cushing's syndrome is more commonly ACTH-independent and caused by an adrenal tumor (adenoma or carcinoma). Of interest, children with Cushing's syndrome from a virilizing adrenal carcinoma may actually present with growth acceleration from the increased adrenal androgen production, rather than the growth failure commonly seen with hypercortisolism. In older children, ACTH-dependent Cushing's from pituitary corticotrophic adenomas (Cushing's disease) accounts for about 50% of cases.

The diagnosis of Cushing's syndrome is confirmed by findings of elevated, non-suppressible levels of glucocorticoid following administration of dexamethasone and elevated levels of urinary free cortisol. Differentiation of ACTH-dependent and independent types, as well as localization of the source of the hypercortisolism, may be achieved through a variety of imaging studies. Treatment of Cushing's syndrome is usually surgical, with the need for subsequent adrenal hormone replacement, and is directed at correction of the primary cause. Medical therapy for Cushing’s disease is usually reserved for those with a contraindication for surgery, since unlike medical therapy surgery offers the potential for a cure.

Disorders of the adrenal medulla Pheochromocytomas are catecholamine-producing tumors of neural crest origin. The vast majority are benign and localized to the adrenal gland, although extra-adrenal pheochromocytomas may occur. The clinical symptoms are directly related to the excess catecholamines released by these tumors and include cold clammy skin, tachycardia, anxiety, agitation, and potentially life-threatening hypertension. Because these tumors release catecholamines episodically, symptoms can occur intermittently. Thus the diagnosis may be difficult to establish and may require multiple investigations. The diagnosis; however, may be confirmed by findings of significantly elevated blood and/or urine levels of catecholamines and their metabolites especially at the time of clinical symptoms. Pheochromocytomas may occur as unilateral or bilateral adrenal tumors (bilateral is more common in children) and either as an isolated or a familial phenomenon, the latter being often part of the Multiple Endocrine Neoplasia (MEN) syndromes. Treatment is directed at surgical removal of the tumor with pre-operative, medical stabilization of the hypertension.

Neuroblastomas, ganglioneuromas, and ganglioneuroblastomas are additional tumors of the adrenal medulla. Although these tumors may excrete catecholamines, dopamine, and its metabolite homovanillic acid (HVA), many are nonfunctional and are often found incidentally during abdominal palpation or imaging performed for other reasons. Treatment is surgical with subsequent chemotherapy as indicated by the pathology findings.

6. True/False: If a child is given large doses (i.e., greater than physiologic replacement) of glucocorticoids for a short period of time (i.e., less than one week) or small doses (i.e. less than physiologic replacement) for any period of time, adrenal function will likely resume shortly after cessation of therapy.